Is LDLR p.Ser554Leu (c.1661C>T) pathogenic?

LDLR p.Ser554Leu (c.1661C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 7 submitters; last evaluated 2025-05-09). AlphaMissense: likely benign (0.1723); Very rare (popmax 0.0011%, sas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ser554Leu (c.1661C>T)?

LDLR p.Ser554Leu (c.1661C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ser554Leu (c.1661C>T) in the general population?

LDLR p.Ser554Leu (c.1661C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LDLR p.Ser554Leu (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.1723) — an in-silico prediction, not a clinical call.

LDLR p.Ser554Leu

c.1661C>T · rs879254976 · VCV251960

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP4 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1661C>T (p.Ser554Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in at least 1 index case with Possible FH by Simon-Broome criteria from Taiwan (PMID 22353362 (Chiou et al., 2012); PMID 33994402 (Huang et al., 2022)), after alternative causes of high cholesterol were excluded. BP4: REVEL = 0.456, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) variant is exonic and at least 50bp downstream from the canonical donor and acceptor site, but it does not create AG/GT. The variant is not predicted to alter splicing.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1723	likely benign
REVEL	0.456	indeterminate
SaProt	LLR -10.75	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,054 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,464 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,054
European (non-Finnish)	0.00017%	589,856

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LDLR
Protein: p.Ser554Leu
Coding: c.1661C>T
MANE Select: NM_000527
dbSNP: rs879254976
Type: single nucleotide variant
Location: chr19:11116168 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 554: a β-strand

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Ser554Trp Uncertain significance ★★★ same residue
LDLR p.Ser554= Likely benign ★★ same residue
LDLR p.Ser554Ter Pathogenic ★ same residue
LDLR p.Ser554fs Pathogenic ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
LDLR c.1705+2T>C Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ldlr-p-ser554leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown